The Study Of Yueju-Ganmaidazao Decoction Confering Antidepressant-like Effects Via NMDA/NO/cGMP Signaling Pathway

Depression is a common neuropsychiatric disorder.With the development of society,the pressure of people’s life has increased,and the incidence rate has been increasing over the years.It is expected that by 2020,depression will become the second most common disease in the world after cardiovascular disease.Depression poses pain to individuals and families,increased the burden on society.The pathogenesis of depression in modern medicine is still in the hypothesis stage.The drug has shortcomings such as slow onset and side effects,and the treatment is not mature.Therefore,the treatment of depression,which is fast,effective and safe,has become an urgent problem to be solved.The classic prescription of traditional Chinese medicine,Yueju-Ganmaidazao Decoction(YG)which has the main effects of promoting qi circulation and removing bad mood,has achieved good results in both basic and clinical antidepressant treatment.However,its antidepressant rapidity and mechanism of action are still unclear.The purpose of this study was to evaluate the rapid antidepressant effect of Yueju-Ganmaidazao Decoction and to determine the role of NMDA/NO/cGMP in the antidepressant effect of Yueju-Ganmaidazao Decoction.Purpose1.Prove that Yueju-Ganmaidazao Decoction has a rapid and lasting antidepressant effect.2.The antidepressant of yueju ganmai dazao decoction is related to NMDA/NO/cGMP signaling pathway.3.Gender difference in antidepressant dosage of Yueju-Ganmaidazao DecoctionMethod:Corresponding to the research purpose,this experiment consists of the following parts:1.Use the tail suspension test(TST)and forced swimming test(FST)to detect the time-effect of antidepressant effect of Yueju-Ganmaidazao Decoction to determine the optimal antidepressant dose.2.Western Blot was used to detect the expression changes of NMDA receptor subunits(NR1,NR2A,NR2B)in hippocampus of mice at different time points after yueju ganmai dazao decoction single administration.3.Using the learned helpless model(LH)and the chronic mild unpredictable stress model(CMS)to detect behavioral changes after a single administration of Yueju-Ganmaidazao Decoction and ketamine for 24 hours,and The impact of NMDA receptor subunits NR1.4.The agonists and antagonists corresponding to NMDA/NO/cGMP were given respectively,and the behavioral test was used to detect whether the antidepression effect of Yueju-Ganmaidazao Decoction was dependent on the inhibitory effect of NMDA/NO/cGMP signaling pathway.5.Mice of different genders were given different doses of Yueju-Ganmaidazao Decoction,followed by tail suspension test(TST)test 30min later and forced swimming test(FST)test 2hr later to detect the difference in YG behavior of different genders with different doses.Results1.After a single dose of 1.0g/kg(low dose),2.0g/kg(medium dose),2.5g/kg(high dose)of Yueju-Ganmaidazao Decoction,The TST and FST immobility time of mice in the 2.5g/kg group were significantly lower compared with that in the blank group.What’s more The antidepressant effect of 2.5g/kg lasted until the 7th day compared with ketamine group.indicating that 2.5 g/kg was the optimal dose for antidepressant.2.The behavioral test was perform.ed on the learned helpless model animals after drug adminstration,YG2.5g/kg reversed the escape latency and the number of failed crossings in mice..After the establishment of CMS model,the SPT of mice was significantly reverse after a single administration of 2.5 g/kg.TST and FST time were shortened,also the feeding latency,and the food intake was increased.Spontaneous activity experiments showed no effect on the total distance and central time of animal activity after administration.3.After single administration of YG2.5 g/kg,The down-regulation of NMDA receptor subunit NR1 in mouse hippocampus started from 30 min and continued to 5 days;while NR2A and NR2B were down-regulated only at 30 min.Subsequently,the change of NR1 was detected on the depression model.YG2.5 g/kg can reverse the increasing effect of NR1 after modeling.4.After the NMDA/NO/cGMP agonist NMDA,L-argine or sildenafil was administered,the antidepressant effect of YG2.5g/kg disappeared;while after the antagonist MK-801,L-NAME,7-nitroindazole(7-NI),Methylene blue(MB)was given,it synergized with YG 1.0 g/kg(sub-effective dose)to play an antidepressant effect.5.different doses of YG were given to male and female mice by intragastric administered.Both TST and FST showed that 2.0g/kg of female mice could reduce the immobility time of behavioral test,while 2.5g/Kg of male mice could be effective.Conclusion1.Yueju-Ganmaidazao Decoction has a rapid anti-depressant effect.2.Yueju-Ganmaidazao Decoction can improve the behavioral characteristics of mice with acute and chronic depression.3.YG2.5g/kg produces antidepressant effects by down-regulating the expression of NMDA/No/cGMP signaling pathways.4.The antidepressant dose of Yueju-Ganmaidazao Decoction has obvious gender differences.